Chronic alcohol abuse results in neuropsychological and brain damage, with significant medical and social costs. Much of the research into these consequences has focussed on how ethanol affects neurons, with a definite bias toward the notions that 1) ethanol is directly and specifically toxic to neurons, and 2) that neuronal pathology accounts for the neuropsychological deficits. Whether or not the former is true for physiological ethanol concentrations, an evolving appreciation of the complexity of glial cells, and their interactions with each other and with neurons, warrant reevaluating at least the first of these assumptions. Current data make a compelling argument that ethanol effects on glial cells might substantially account for neuronal pathology via metabolic, systemic, trophic, or structural perturbances. Our long- term goal is to determine the mechanisms by which chronic ethanol produces brain damage. Accordingly, we have designed two studies into the effects of long term ethanol on glial cells in a well-studied brain structure, the hippocampus, where the effects of ethanol on neurons are well documented. In the first study, we plan to label hippocampal neurons, astrocytes, oligodendrocytes, and microglia with specific cell type markers, and compare the number, size, shape and staining intensity of each type between rats exposed to ethanol for 20 wks. and nutritional control rats. Once we have established the respective in vivo effects, we will employ a similar experimental design to evaluate the potential utility of an organotypic tissue culture model system from the same brain region. This culture system is viable for sufficiently long periods that chronic ethanol studies are possible, and maintains the natural tissue architecture to a high degree. It is anticipated that ethanol will have significant and selective effects on glial cells, and that the in vitro model system will offer distinct advantages for future studies into the mechanisms associated with these effects.